1. Field of the Invention
The invention relates to nucleoside phosphonate compounds and methods of synthesis, isomerization and uses thereof.
2. Related Art
Acyclic nucleoside phosphonates (ANPs) are broad spectrum antiviral agents that are highly potent against orthopox viruses, including cowpox, vaccinia, and variola (smallpox) virus. The prototype member of the ANPs is (S)-9-(3hydroxy-2-phosphonyl-methoxypropyl)adenine ((S)-HPMPA, 1) (FIG. 1), first described 1986 for its activity against DNA viruses [1]. Its cytosine analogue, (S)-HPMPC (cidofovir, 2) [2] (FIG. 1) has been shown to have similar therapeutic potential against virtually all DNA viruses as well as other adeno-, papiloma-, polyoma-, and poxvirus infections. Cidofovir has been formally licensed since 1996 in the clinic as Vistide® for the treatment of AIDS patients infected with cytomegalovirus (CMV). The potential use of variola virus (the etiological agent for smallpox) and other orthopox viruses as bioterrorism weapon has stimulated efforts to develop new drugs for the treatment of these pathogenic viruses.
Cidofovir has so far been the only drug approved to be used in an emergency treatment of smallpox outbreak. Although (S)-HPMPC is highly potent in vitro and in animal model infections, it has low oral bioavailability due to the presence of ionized at physiological pH phosphonic acid group. Therefore, (S)-HPMPC and other ANP are effective only when delivered intravenously [3]. This condition limits therapeutic scope of drugs especially under disruptive conditions of a large-scale biowarfare attack or in limited medical facilities of rural areas. Moreover, after intravenous injection drugs of this class tend to accumulate in the kidney leading to severe renal toxicity and it is therefore necessary to increase hydration and co-administer probenecid to prevent nephrotoxicity [4-6]. Thus, there is a pressing need for a new effective orally bioavailable drugs active against orthopox viruses.